This invention relates to testing and treatment of autoimmune diseases such as type I diabetes. The invention takes advantage of a link we have discovered between type I diabetes and major histocompatibility complex (MHC) class I molecules, or HLA class I molecules, as they will be referred to herein.
T-lymphocytes recognize self or foreign proteins in the binding groove of HLA, resulting in HLA-restricted immune responses. Peptides in the extracellular compartment are taken up by antigen presenting cells by endocytosis and subsequently are presented as peptides in association with HLA Class II complexes. These HLA Class II-peptide complexes are recognized by CD4+helper cells. In contrast, endogenously synthesized antigens, or "self peptides", are transported into the endoplasmic reticulum where they preferentially bind to HLA class I and these HLA-I-peptide complexes are subsequently recognized by CD8+suppressor or cytotoxic T-cells. HLA class I expression is normally universally present on all cells.
Recently, a series of experiments have identified transmembrane transporter genes involved in the process of transportation of cytosolic peptides into the endoplasmic reticulum, and mapping studies have localized their chromosomal location within the HLA class II region. These peptide supply factor genes (also known as ATP-dependent transporter protein-encoding genes, Tap-1 and Tap-2), are members of the multidrug resistant family of transporters and are highly conserved between species (e.g., see Monaco, Immunology Today 13:173-179, 1992). Their identification has been feasible by a series of induced mutant cell lines which lack surface HLA class I (i.e., do not "present" HLA class I) by virue of deletions in either or both of the endogenous Tap-1 and Tap-2 genes (Monaco et al., Science 250:1723-1726, 1990; Deverson et al., Nature 348:738-741, 1990; Trowsdale et al., Nature 348:741-744, 1990; Spies et al., Nature 348:744-747, 1990).
Type I diabetes is an autoimmune disease characterized by T-cell mediated destruction of the beta cells in the islets of Langerhans, accompanied by an immune response to a diversity of self peptides. Similar to other autoimmune diseases, IDDM has a genetic predisposition. In the absence of an identified specific gene abnormality, the strongest genetic associations have been between IDDM and genes encoding the HLA class II polypeptides (Todd et al., Nature 329:599-604; Thomson et al., Am. J. Hum. Genet. 43:799-816; Busch et al., Expl. J. Med. 322:1836-1841). Similar linkage has been shown for other autoimmune diseases, including Graves' disease, Hashimoto's thyroiditis systemic lupus erythematosis and autoimmune adrenal insufficiency (Moccs et al., N. Expl. J. Med. 399:133; Sveigaard et al., Immunol. Rev. 70:193-218; Macharen et al., J. Clin. Endocrin. 62:455-459). The strong association between autoimmune disease and HLA class II genes has suggested that abnormalities in HLA class II gene products play a central pathogenetic role in autoimmune diseases.
Humans at risk for type I diabetes can be identified years prior to hyperglycemia by the abnormal occurrence of autoantibodies to insulin, islet cells, glutamic acid decarboxylase, as well as many other autologous proteins. The autoantibody patterns predict eventual disease progression and/or risk. A recent analysis of "prediabetics" as well as discordant diabetic type I identical twins revealed a T-cell developmental defect controlled by abnormal autologous presentation of self antigens which was predictive of disease progression.